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PMID: 17804842 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.

The New England journal of medicine ·Vol. 357 ·No. 10 ·2007-09-06 ·Pages 977-86

Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK

Abstract

Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

MeSH Terms
Arthritis, Rheumatoid/genetics Case-Control Studies Chromosome Mapping Chromosomes, Human, Pair 2 Genetic Linkage Genetic Predisposition to Disease Genotype Haplotypes Humans Lupus Erythematosus, Systemic/genetics Polymorphism, Single Nucleotide Risk STAT4 Transcription Factor/genetics
Chemicals
STAT4 Transcription Factor
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Remmers Elaine F
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
Plenge Robert M
Lee Annette T
Graham Robert R
Hom Geoffrey
Behrens Timothy W
de Bakker Paul I W
Le Julie M
Lee Hye-Soon
Batliwalla Franak
Li Wentian
Masters Seth L
Booty Matthew G
Carulli John P
Padyukov Leonid
Alfredsson Lars
Klareskog Lars
Chen Wei V
Amos Christopher I
Criswell Lindsey A
Seldin Michael F
Kastner Daniel L
Gregersen Peter K
References (50)
50 references, click to expand
  1. Efficiency and power in genetic association studies.
    Nat Genet. 2005 Nov;37(11):1217-23 PMID: 16244653
  2. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.
    Nat Genet. 2004 Apr;36(4):337-8 PMID: 15004560
  3. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.
    Am J Hum Genet. 2005 Dec;77(6):1044-60 PMID: 16380915
  4. The New York Cancer Project: rationale, organization, design, and baseline characteristics.
    J Urban Health. 2004 Jun;81(2):301-10 PMID: 15136663
  5. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.
    Am J Hum Genet. 2004 Aug;75(2):330-7 PMID: 15208781
  6. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.
    Arthritis Rheum. 2004 Oct;50(10):3085-92 PMID: 15476204
  7. Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23.
    Arthritis Rheum. 2004 Oct;50(10):3203-10 PMID: 15476245
  8. The 1982 revised criteria for the classification of systemic lupus erythematosus.
    Arthritis Rheum. 1982 Nov;25(11):1271-7 PMID: 7138600
  9. The immunogenetics of rheumatoid arthritis.
    Springer Semin Immunopathol. 1992;14(1):59-78 PMID: 1440198
  10. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14869-74 PMID: 9843982
  11. The genetics revolution and the assault on rheumatoid arthritis.
    Arthritis Rheum. 1999 Jun;42(6):1071-9 PMID: 10366098
  12. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.
    Immunol Rev. 2004 Dec;202:139-56 PMID: 15546391
  13. Haploview: analysis and visualization of LD and haplotype maps.
    Bioinformatics. 2005 Jan 15;21(2):263-5 PMID: 15297300
  14. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes.
    Am J Hum Genet. 2005 Apr;76(4):561-71 PMID: 15719322
  15. Demonstrating stratification in a European American population.
    Nat Genet. 2005 Aug;37(8):868-72 PMID: 16041375
  16. Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs.
    Ann N Y Acad Sci. 2005 Nov;1058:87-95 PMID: 16394128
  17. Genome scan meta-analysis of rheumatoid arthritis.
    Rheumatology (Oxford). 2006 Feb;45(2):166-70 PMID: 16278286
  18. Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis.
    Ann Neurol. 2006 Feb;59(2):404-7 PMID: 16437561
  19. Genome-wide meta-analysis for rheumatoid arthritis.
    Hum Genet. 2006 Jul;119(6):634-41 PMID: 16612613
  20. High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33.
    Genes Immun. 2006 Jun;7(4):277-86 PMID: 16691188
  21. PTPN22: setting thresholds for autoimmunity.
    Semin Immunol. 2006 Aug;18(4):214-23 PMID: 16731003
  22. Principal components analysis corrects for stratification in genome-wide association studies.
    Nat Genet. 2006 Aug;38(8):904-9 PMID: 16862161
  23. European population substructure: clustering of northern and southern populations.
    PLoS Genet. 2006 Sep 15;2(9):e143 PMID: 17044734
  24. Genetics of autoimmune diseases--disorders of immune homeostasis.
    Nat Rev Genet. 2006 Dec;7(12):917-28 PMID: 17139323
  25. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
    Science. 2006 Dec 1;314(5804):1461-3 PMID: 17068223
  26. NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation.
    J Leukoc Biol. 2007 Jan;81(1):355-63 PMID: 17046972
  27. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
    Am J Hum Genet. 2007 Feb;80(2):273-90 PMID: 17236132
  28. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis.
    J Immunol. 2007 Mar 15;178(6):3427-36 PMID: 17339437
  29. T(H)-17 cells in the circle of immunity and autoimmunity.
    Nat Immunol. 2007 Apr;8(4):345-50 PMID: 17375096
  30. Stat3 and Stat4 direct development of IL-17-secreting Th cells.
    J Immunol. 2007 Apr 15;178(8):4901-7 PMID: 17404271
  31. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort.
    Genes Immun. 2007 Jun;8(4):279-87 PMID: 17344889
  32. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus.
    PLoS Med. 2006 Dec;3(12):e491 PMID: 17177599
  33. Association of STAT4 with rheumatoid arthritis in the Korean population.
    Mol Med. 2007 Sep-Oct;13(9-10):455-60 PMID: 17932559
  34. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles.
    Arthritis Rheum. 2005 Dec;52(12):3813-8 PMID: 16320316
  35. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins.
    Arthritis Rheum. 2000 Jan;43(1):30-7 PMID: 10643697
  36. Hopkins Lupus Cohort. 1999 update.
    Rheum Dis Clin North Am. 2000 May;26(2):199-213, v PMID: 10768209
  37. Statistics notes. The odds ratio.
    BMJ. 2000 May 27;320(7247):1468 PMID: 10827061
  38. Association mapping in structured populations.
    Am J Hum Genet. 2000 Jul;67(1):170-81 PMID: 10827107
  39. Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2.
    Am J Hum Genet. 2000 Dec;67(6):1460-9 PMID: 11078476
  40. Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses.
    J Immunol. 2001 Apr 1;166(7):4446-55 PMID: 11254700
  41. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms.
    J Immunol. 2002 Sep 15;169(6):3345-52 PMID: 12218156
  42. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6 PMID: 12213961
  43. HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias.
    Arthritis Rheum. 2002 Sep;46(9):2320-9 PMID: 12355479
  44. Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling.
    J Immunol. 2002 Oct 15;169(8):4388-98 PMID: 12370372
  45. Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.
    J Dermatol Sci. 2002 Nov;30(2):161-6 PMID: 12413772
  46. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.
    Nat Genet. 2003 Feb;33(2):177-82 PMID: 12524541
  47. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.
    Arthritis Rheum. 2003 Apr;48(4):906-16 PMID: 12687532
  48. Predicting mortality in patients with rheumatoid arthritis.
    Arthritis Rheum. 2003 Jun;48(6):1530-42 PMID: 12794820
  49. Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice.
    J Immunol. 2003 Aug 1;171(3):1564-71 PMID: 12874250
  50. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases.
    Ann Rheum Dis. 2003 Sep;62(9):835-41 PMID: 12922955
Article Info
Journal
The New England journal of medicine
Abbr.
N Engl J Med
ISSN
1533-4406
DOI
10.1056/NEJMoa073003
Published
2007-09-06
Pages
977-86
Language
English
Region
United States
NLM ID
0255562
PMCID
PMC2630215
Subset
IM
Grants
NCRR NIH HHS · M01 RR000079 · United States
NIAMS NIH HHS · R01 AR050267 · United States
NIAMS NIH HHS · R01 AR-44804 · United States
NIAID NIH HHS · K08 AI055314-03 · United States
NCRR NIH HHS · M01 RR018535 · United States
NIAID NIH HHS · N01AI95386 · United States
NIAMS NIH HHS · R01 AR044422 · United States
NCRR NIH HHS · 5-M01-RR-00079 · United States
NIAID NIH HHS · K08 AI055314-02 · United States
NIAID NIH HHS · K08 AI055314-01A1 · United States
NIAMS NIH HHS · R01 AR44422 · United States
NIAID NIH HHS · K08 AI055314-05 · United States
NIAMS NIH HHS · N01-AR-2-2263 · United States
NIAID NIH HHS · N01-AI95386 · United States
NIAMS NIH HHS · R01 AR052300 · United States
NIAMS NIH HHS · N01-AR-1-2256 · United States
NIAID NIH HHS · K08 AI055314 · United States
NIAID NIH HHS · K08 AI055314-04 · United States
Corrections
CommentIn
PMID: 18077818
External Links
PubMed source DOI: 10.1056/NEJMoa073003 PMC Full Text View journal details
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